Ischemia may be defined as the loss of blood flow to a tissue. Cerebral ischemia, also known as stroke, is the interruption or reduction of blood flow in the arteries feeding the brain. Loss of blood flow to a particular vascular region is known as focal ischemia; loss of blood flow to the entire brain, global ischemia. When deprived of blood, and thus, oxygen and glucose, brain tissue may undergo ischemic necrosis or infarction. The metabolic events thought to underlie such cell degeneration and death include: energy failure through ATP depletion; cellular acidosis; glutamate release; calcium ion influx; stimulation of membrane phospholipid degradation and subsequent free-fatty-acid accumulation; and free radical generation. Examples of methods for the treatment of stroke have been described in U.S. Pat. Nos. 5,872,108; 5,914,112; 5,945,432; 6,063,819 and 6,068,844.
Vitamin E (alpha-tocopherol) and closely related compounds have long been thought to act as antioxidants. Halliwell (1996) Ann. Rev. Nutr. 16:33-50; Diplock et al. (1998) Br. J. Nutr. 80: S77-112. Alpha-tocopherol can prevent peroxidation in vitro, and this function can be replaced by other antioxidants. However, additional functions for vitamin E seem likely, since other antioxidants cannot relieve all the symptoms of vitamin E deficiency. There is increasing evidence that tocopherols are involved in the control of cell proliferation and differentiation. Traber et al. (1995) Am. J Clin. Nutr. 62: 1501S-1509S. Alpha-tocopherol also functions as a scavenger of active nitrogen species (Halliwell et al. (1992) FEBS Lett. 313:62-66) and a gamma-tocopherol metabolite is an alleged natriuretic (Wechter et al. (1996) Proc. Natl. Acad. Sci. USA 93:6002-6007). See also U.S. Pat. Nos. 6,150,402; 6,083,982; 6,048,891, and 6,242,479 specifically incorporated herein in their entirety. Alpha-tocopherol has been alleged to have an effect on cerebral ischemia. Yamamoto et al., 1983, Stroke, vol. 14:977-982; Hara et al., 1990, Brain Research, vol. 510: 335-338; and Altura, et al., 1996, Neuroscience Letters, vol. 220:207-210. In addition, alpha-tocopherol or its quinone derivatives may be involved in fatty acid desaturation. Infante (1986) Mol. Cell. Biochem. 69:93-108; Infante et al. (1998) FEBS Lett. 431:1-6. An additional major role of dietary alpha-tocopherol may be as a precursor of its D-alpha-tocopherolquinone metabolite whose semiquinone radical is required as an essential enzyme cofactor by carnitine-dependent, channeled mitochondrial fatty acid desaturases. Infante (1999) FEBS Lett. 446:1-5.
Tocopherols, while generally similar in overall chemical structure, may vary in biological function. Alpha-tocopherol is generally considered the most biologically active form of vitamin E; it is also the most abundant in adult human serum. Neuzil et al. (1998) Card. Drugs. Ther. 12:421-423; Strohschein et al. (1998) Anal. Chem. 70:13-18; Gonzalez (1990) Med. Hypothes. 32:107-110. Alpha-tocopherol has a greater antioxidant activity than the other tocopherols. Fukuzawa et al. (1982) Lipids 17:511-13. Alpha-tocopherol, but not beta-tocopherol, inhibits protein kinase C function. Ricciarelli et al. (1998) Biochem. J. 334:243-249. However, both alpha- and beta-tocopherol inhibit porcine pancreatic phospholipase A2 activity. Grau et al. (1998) Chem. Phys. Lipids 91:109-118. Alpha-, beta-, gamma- and delta-tocopherol were all able to inhibit superoxide generation by neutrophils. Kanno et al. (1996) Free Radic. Res. 24:181-189. Delta-tocopherol has only one hundredth of the activity of natural alpha-tocopherol in the Evans resorption sterility test for vitamin E.
In the treatment of cerebral ischemia, free radical scavengers/antioxidants have been used to improve cerebral blood flow and/or neurological outcome. In general, the effects of these compounds on infarct volume have been inconsistent. U.S. Pat. No. 5,872,108. For example, superoxide dismutase inhibitors have been found to reduce infarct volume only when injected intracerebroventricularly. See, Kinouchi et al. (1991) Proc. Natl. Acad. Sci. USA 88:11158-11162. Other compounds, such as lubeluzole, have been shown to have clinical benefit for cerebral ischemia but with a very narrow margin of safety. Diener et al. (1995) Stroke 26:30.
Cerebral ischemia is one of the major causes of human neurological morbidity and mortality with poor prognosis associated with stroke recovery. Thus, a need remains for identification of effective compositions and methods which aid in the survival and recovery of cells during injury associated with cerebral ischemia or for mammalian subjects at risk for injury associated with cerebral ischemia.
The disclosure of all patents and publications cited herein are incorporated by reference in their entirety.